Lyme disease is the most common tick-borne disease in temperate regions of the northern hemisphere, affecting large areas of North America and Eurasia.[1] In North America, Lyme disease is caused by the spirochete Borrelia burgdorferi and cases are concentrated in the Northeast, upper Midwest and Mid-Atlantic. Recently, CDC and state health investigators estimated that 288,000 new infections occurred in the United States in 2008.[2] In certain high-risk communities, studies suggest that the incidence of new cases may be 3%, with cumulative prevalence as high as 7-17%.[3] As the geographic range of the tick vector, and the mouse and deer hosts expands, the impact of Lyme and other tick borne-diseases is likely to grow.[4]
The hallmark of early Lyme disease is a cutaneous lesion, erythema migrans (EM), which occurs with or without symptoms of infection such as fever, arthralgias, fatigue, headache or neck pain.[5] Within days to weeks, B. burgdorferi may disseminate from the site of skin inoculation through the blood or tissues and spread systemically to other areas of the skin, musculoskeletal, cardiac and neurologic systems. More than 50% of patients with EM are found to have positive PCR or blood culture results at this stage.[6, 7] In the absence of effective antibiotic treatment, the adaptive immune response does not reliably eradicate infection, with small numbers of spirochetes able to persist in certain tissues.[8] If untreated, as many as 60% of patients will have a clinical relapse months to years later with manifestations of late Lyme arthritis or less commonly in the United States, neurologic disease.[9]
Antibiotic treatment of early Lyme disease speeds resolution of EM and is effective in preventing later objective manifestations. However, treatment at later stages may be more difficult. Approximately 10% of late Lyme arthritis patients have persistent or recurrent objective findings termed post-treatment antibiotic refractory disease. This is thought to be due to autoimmune-mediated inflammation that occurs in genetically susceptible individuals, especially those with Toll-like receptor 1 polymorphism and/or the HLA-DR4 alleles.[10]
Approximately 10% of patients with diagnosed and treated early Lyme disease have persistent symptoms of fatigue, arthralgias, sleep disruption or cognitive complaints following antibiotic treatment. These post-treatment symptoms may be mild and limited, or severe and chronic. When post-treatment symptoms last six months or longer and impair life functioning, patients meet the case definition for post-treatment Lyme disease syndrome (PTLDS).[1, 11, 12] Studies have suggested a severe initial illness,[13, 14] delayed treatment,[13] neurologic involvement,[1, 15] or suboptimal antibiotic therapy [15, 16] as potential risk factors for development of PTLDS.
The pathophysiology of PTLDS is unknown, but theories include persistence of bacteria and/or spirochetal antigens after antibiotic therapy, as suggested by animal models.(18,19) Immune system abnormalities independent of ongoing infection may also be an important mechanism. Retained spirochetal antigens have been hypothesized to lead to immune dysregulation of CD4+ T cell subsets in antibiotic refractory arthritis.[19] Anti-neural antibodies have been found in one sample of patients with PTLDS.[20]
As described below, we examined serum levels of sixty-five immune mediators among patients with acute Lyme disease and identified a clear associated signature relative to normal controls, including increased CXCL9, CXCL10, and CCL19.[21] We then sought to examine the relationship of these immune mediators to patient clinical response over time, from pre-treatment diagnosis of early Lyme disease up to one year following completion of antibiotic treatment. We hypothesize that those individuals who meet the case definition of PTLDS, as compared to those that don't meet criteria and normal controls, will have persistent elevations of specific immune mediators following antibiotic treatment.